Focused on improving relapsed/refractory T-ALL patient outcomes, Maciocia et al. identified CD21 as a promising target for CAR T cell therapy. Targeting membrane-distal regions of the highly glycosylated CD21 was ineffective, while Fab-CARs designed to bind membrane-proximal CD21 epitopes elicited robust activity against low-density T-ALL cell lines, primary tumors, and PDX models. Efficacy was attributed to enhanced stability, and partially to reduced surface expression. Furthermore, pharmacological inhibition of PI-3 kinase upregulated CD21 expression in T-ALL and increased the potency of anti-CD21 CAR T cells in vitro and in vivo.
Contributed by Katherine Turner
ABSTRACT: Patients with relapsed/refractory (r/r) T cell acute lymphoblastic leukemia (T-ALL) have a dismal prognosis, highlighting the urgent need for effective therapies. Chimeric antigen receptor (CAR)-T cell approaches targeting pan-T cell antigens may be limited by T cell aplasia and fratricide, necessitating "rescue" allogeneic hematopoietic stem cell transplantation. In this study, we identify CD21, a pan-B cell marker, as a promising target for T-ALL immunotherapy. CD21 is expressed in 50% of T-ALL cases at diagnosis but in fewer than 10% of mature T cells. We observed that CAR-T cells targeting membrane-distal CD21 epitopes were ineffective, likely because of the bulky, glycosylated nature of the antigen. However, when we engineered CAR-T cells to target membrane-proximal CD21 epitopes using an antigen-binding fragment (Fab)-CAR design, we demonstrated robust activity against T-ALL cell lines, primary tumors, and patient-derived xenografts in both in vitro and in vivo models. The enhanced efficacy of this Fab-CAR design was driven by its high stability and reduced surface expression, addressing limitations of traditional CAR constructs. In addition, pharmacological inhibition of the phosphatidylinositol 3-kinase axis up-regulated CD21 expression in T-ALL, further enhancing the potency of anti-CD21 CAR-T cells in vitro and in a patient-derived xenograft in vivo model. This study establishes CD21 as a viable CAR-T target and highlights advances in CAR design for bulky antigens, as well as the potential for pharmacological strategies to augment target expression. Anti-CD21 CAR-T cells represent a promising therapeutic option for improving outcomes for patients with T-ALL.
Author Info: (1) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (2) Department of Haematology, Cancer Institute, University Coll
Author Info: (1) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (2) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (3) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (4) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (5) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (6) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (7) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (8) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (9) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (10) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (11) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (12) Autolus Ltd., Mediaworks, 191 Wood Lane, White City, London W12 7FP, UK. (13) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (14) Department of Haematology, Ospedale Papa Giovanni XXIII, Piazza OMS 1, 24127 Bergamo, Italy. (15) Autolus Ltd., Mediaworks, 191 Wood Lane, White City, London W12 7FP, UK. (16) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (17) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (18) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (19) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (20) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. (21) Department of Haematology, Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
